Programmed cell death, or apoptosis, is important for the development of most organs also for adult tissue homeostasis and remodeling. However, an inexorable loss of terminally differentiated heart muscle cells is a crucial causal factor for heart failure, the current leading cause of death in developed countries. Here, we demonstrate that HSG (also named mitofusin-2), a mitochondria protein, is a major determinant of oxidative stress-mediated cardiomyocyte apoptosis. Myocardial infarction profoundly elevates endogenous HSG expression and myocyte apoptosis in vivo via a reactive oxygen species (ROS)-dependent mechanism. Similarly, oxidative stress with H2O2 concurrently increases HSG expression and apoptosis in cultured rat cardiomyocytes. Furthermore, adenoviral gene transfer-mediated overexpression of HSG is sufficient to suppress both basal and serum-stimulated Akt activation, and triggers robust cardiomyocyte apoptosis. The HSG-induced apoptosis is fully abrogated by inhibition of caspase-9 but not caspase-8, and by expression of a constitutively active PI3K mutant to activate Akt or a mitochondrial antiapoptotic protein, Bcl-xL, indicating that HSG promotes cardiomyocytes apoptosis via inhibition of the PI3K-Akt cell survival signaling and the resultant activation of the primary mitochondrial apoptotic pathway. Importantly, siRNA-mediated HSG silencing protects cells against oxidative stress-induced apoptosis. The present results indicate that cardiac HSG functions as a major determinant of heart muscle cell apoptosis in response to ischemia and oxidative stress, via inhibiting the primary cell survival signal, Akt, resulting in activation of the mitochondrial cell death pathway. Importantly, increased cardiac HSG expression is both necessary and sufficient for oxidative stress-induced heart muscle cell apoptosis, suggesting that HSG deregulation may be a crucial pathogenic element and a promising therapeutic target for heart failure.[unreadable] [unreadable] Additionally, in vascular smooth muscle cells (VSMCs), HSG functions as a powerful cell proliferation suppressor (Chen et al. Nature Cell Biology, 6:872-883, 2004). When overexpressed, HSG triggers VSMC apoptosis (Guo et al., Circ. Res. 2007, in press). First, multiple death-inducing stimuli, including oxidative stress with H2O2, inhibition of PKC with staurosporine, activation of PKA with forskolin, and serum deprivation, concurrently elevated Mfn-2 expression and induced VSMC apoptosis. Second, overexpression of HSG triggered apoptosis of VSMCs in culture and in balloon-injured rat carotid arteries as well, thus contributing to HSG-mediated prevention of neointima formation after angioplasty, while HSG silencing protected VSMCs against H2O2 or HSG overexpression induced apoptosis, indicating upregulation of HSG is necessary and sufficient for oxidative stress mediated VSMC apoptosis. Finally, HSG proapoptotic effect was independent of its role in mitochondrial fusion, but mediated by activation of the mitochondrial apoptotic pathway. The concurrent antiproliferative and proapoptotic effects mark HSG as a potential therapeutic target in treating cardiovascular proliferative disorders, because overgrowth of VSMCs is a pivotal etiological factor in the development of atherosclerosis and restenosis after angioplasty.